Phosphotidylinositol 3-kinase (PI3K) is both a phospholipid kinase, and a protein serine/threonine kinase as described in Carpenter et al, Mol. Cell. Biol. 13:1657-1665 (1993). PI3K is an enzyme stimulated by growth factors that is responsible for phosphorylating phosphotidylinositol (PI) at the D-3′ position of the inositol ring as described in Whitman et al, Nature 332:644-646 (1988). PI3K association with Src-like or receptor tyrosine kinases also implicates PI3K in the oncogenic or mitogenic responses induced by these protein kinases, as described in Cantley et al, Cell 64:281-302 (1991), Escobedo and Williams, Nature 335:85-87 (1988), and Fantl et al, Cell 69:413-423 (1992).
Previously, studies to elucidate the downstream effects of PI3-kinase activation have been conducted with receptor mutants constructed to alter the signal transduction of PI3K, or by constructing mutant oncogenes to study a PI3K inducible oncogenic response. The failure of receptor mutants of platelet derived growth factor (PDGF) receptor to activate PI3K has been correlated with deficiency of the receptor mutants in triggering a mitogenic response. Similarly, mutants of certain oncogenes have failed to trigger the oncogenic transformation inducible by the parent oncogene. A method was subsequently constructed to facilitate downstream effects of PI3K directly, without growth factor activation to determine whether PI3K was distinctly involved oncogenesis and mitogenesis. The results elucidated that PI3K can be directly or indirectly responsible for many cellular processes, such as mitogenesis and oncogenesis, as well as histamine secretion, neutrophil activation, platelet activation, cell migration, glucose transport, antilipolysis, and vesicle sorting.
With the many regulatory responses associated with PI3-kinase, which is known to be involved in signal cascades involving other well known oncogenic proteins, such as receptor tyrosine kinases (e.g., VEGF-RTK), it would be highly desirable to produce small molecules capable of modulating, e.g. inhibiting, the activity of PI3-kinase.
It is an object of this invention to provide potent inhibitors of PI3K. It is further an object of the instant invention to provide compounds alone or in combination with other known agents to modulate cellular proliferation in patients in need thereof. Additionally, it is an object of this invention to provide medicaments for use in the treatment cancer.